1. Field of the Invention
The present invention belongs to the fields of pharmacology and medicine and provides methods to determine which patients will develop elevated serum cholesterol levels during treatment with an immunosuppressant drug. In particular, this invention relates to the use of genomic analysis to identify patients at risk for developing increased cholesterol levels during immunosuppressant drug therapy and to methods to determine optimal treatment strategies for these patients.
2. Description of the Related Art
Immunosuppressant drugs have many important applications in modern medicine. These drugs are used to suppress the rejection of transplanted organs, including hearts, lungs and kidneys to prolong the useful life of the transplanted organ. In addition, immunosuppressant drugs are used to treat a wide variety of other diseases such as autoimmune diseases, myocarditis and rheumatoid arthritis. However, the immunosuppressant drugs have numerous, and sometimes severe, side effects which include causing cancer and lymphomas and producing a variety of toxic effects on internal organs, such as the kidney.
Because of the toxic effect of the immunosuppressant drugs, there has been a great deal of effort to develop less toxic alternatives and to find drugs whose mechanism of action differs from that of the other immunosuppressant drugs so that synergistic combinations can be used with fewer overall side effects.
Recently an anti-fungal, anti-tumor and immunosuppressive antibiotic called rapamycin (also known as sirolimus and RAPAMUNE™) has been found to be effective at inhibiting allograft rejection. Rapamycin has a mechanism of action that is unique and markedly different from that of other immunosuppressant drugs. Rapamycin and its derivatives, such as everolimus (CERTICAN™)(RAD) act by inhibiting the biochemical pathways involved in the G1-S phase progression of activated T cells in a Ca2+ independent manner. See Schuler et al., Transplantation, Vol. 64, pp. 36-42 (1997). In this way, rapamycin derivatives such as everolimus block cytokine signal transduction rather than blocking the production of cytokines as in the case of other immunosuppressant drugs, such as cyclosporine.
Rapamycin and its derivatives and mycophenolic acid are effective immunosuppressant drugs, however, in some patients the administration of these drugs has been found to cause elevations in serum cholesterol and triglycerides, i.e., hypercholesterolemia and hyperlipidemia. Both of these conditions are risk factors for coronary artery disease (CAD) and atherosclerosis in general, especially in diabetic patients.
Hypercholesterolemia itself, is a common condition and can be treated with several major classes of drugs. These include the HMG-CoA reductase inhibitors or the so-called statins, the bile acid-binding resins and nicotinic acid.
Increased serum cholesterol levels during treatment with an immunosuppressant drug, such as rapamycin or its derivatives including, but not limited to, everolimus (CERTICAN™)(RAD) or with mycophenolic acid, is a serious adverse side effect. This is especially true for organ transplant patients since these patients require long-term (generally life long) treatment. The increase in serum cholesterol levels varies widely from patient to patient and prior to the present invention it was not possible to predict which patients would develop these increases. Thus, there is a need for methods to predict which patients will experience elevations in serum cholesterol when immunosuppressant drugs, such as rapamycin and its derivatives or mycophenolic acid are administered to patients, especially for long-term use.